Provided herein are improved compounds for binding to and imaging collagen. Also provided herein are pharmaceutical compositions containing the compounds provided herein.
Collagens are a class of extracellular matrix proteins that represent 30% of total body protein and shape the structure of tendons, bones, and connective tissues. Abnormal or excessive accumulation of collagen in organs such as the liver, lungs, kidneys, or breasts, and vasculature can lead to fibrosis of such organs (e.g., myocardial fibrosis, heart failure, nonalcoholic steatohepatitis of the liver (also known as NASH), cirrhosis of the liver, primary biliary cirrhosis), lesions in the vasculature or breasts, collagen-induced arthritis, Muscular dystrophy, scleroderma, Dupuytren's disease, rheumatoid arthritis, and other collagen vascular diseases. It would be useful to have diagnostic agents that could assist in the treatment or diagnosis of such disorders.
Compounds and pharmaceutical compostions for collagen imaging have been previously disclosed in U.S. Pat. No. 8,034,898 and various publications, including Kolodziej, et al., “Peptide optimization and conjugation strategies in the development of molecularly targeted magnetic resonance imaging contrast agents.” Methods Mol Biol. 2014; 1088: 185-211, Helm, et al. “Postinfarction myocardial scarring in mice: molecular magnetic resonance (MR) imaging with use of a collagen-targeting contrast agent.” Radiology. 2008 June; 247(3): 788-96, and Caravan et al. “Collagen-targeted MRI contrast agent for molecular imaging of fibrosis.” Angew Chem Int Ed Engl. 2007; 46(43): 8171-3.
However, improved compounds that exhibit superior binding to collagen of animals used in preclinical studies (especially rodent, canine) along with greater in vivo uptake into collagen tissue and robust imaging enhancement are needed. In addition, because of the association of free gadolinium(III) ions with Nephrogenic Sclerosing Fibrosis (NSF, Thomsen H S. (2009) Nephrogenic systemic fibrosis: history and epidemiology Radiol Clin North Am. 47(5): 827-31), there is a need for new derivatives that do not require gadolinium chelates.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
Other features and advantages of the disclosure will be apparent from the following detailed description and figures, and from the claims.